Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Coagulants

Bevacizumab

Cisplatin

Chlorotrianisene

Liver Extracts

Gelatin Sponge, Absorbable

Ethiodized Oil

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Participants received bevacizumab 5 mg/kg intravenously every 2 weeks and within 24-48 hours prior to each transarterial chemoembolization (TACE) until disease progression or unmanageable toxicity. TACE was conducted for 4 sessions at 8-10 week intervals.

Bevacizumab was supplied as a sterile liquid in single-use vials.

TACE was conducted by the transfemoral artery approach with selective cannulation of the artery supplying the tumor. Cisplatin mixed with Lipiodol in a 1 mg:1 mL ratio was infused intra-arterially up to a maximum dose of 30 mg, depending on tumor size, followed by embolization of the artery using Gelfoam particle until the blood flow slowed. Bilobar lesions were treated by separate catheterization of right and left hepatic arteries followed by injection of the cisplatin-Lipiodol mixture and embolization.

Patients with stable disease or a partial response after 4 TACE sessions could be given further TACEs upon the investigator's discretion until there was evidence of progressive disease or contraindication due to severe complication or technical failure to perform the TACE.

Transarterial chemoembolisation (TACE)

Clinical Trials

This single-arm, open-label study assessed the efficacy and safety of Avastin (bevacizumab) treatment combined with transarterial chemoembolisation (TACE) in patients with localized unresectable liver cancer. Patients were treated with TACE at 8 or 10 week intervals for 4 sessions (continuation depended on investigator's discretion). Avastin 5 mg/kg intravenously was administered 24-48 hours prior to each TACE session and every 2 weeks between the TACE sessions until disease progression.

A Study of Avastin (Bevacizumab) and Transarterial Chemoembolisation (TACE) Treatment in Patients With Liver Cancer

A Phase II Single Arm, Multi-centre Study of Bevacizumab (Avastin®) Pre- and Post-transarterial Chemoembolisation (TACE) Treatment for Localized Unresectable Hepatocellular Carcinoma (HCC)

Progression-free survival was defined as the time from the first administration of study drug to the first documented disease progression or death, whichever occurs first. Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the unequivocal progression of existing non-target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions at Baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter for all target lesions will be calculated and reported as the Baseline sum longest diameter.

An objective response was defined as a complete response or a partial response. A complete response was defined as the disappearance of all target lesions. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the Baseline sum longest diameter. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions at Baseline. All other lesions (or sites of disease) should be identified as non-target lesions. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter for all target lesions will be calculated and reported as the Baseline sum longest diameter.

Time to progression was defined as the time from the first administration of study drug to the first documented disease progression. Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the unequivocal progression of existing non-target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions at Baseline. All other lesions (or sites of disease) should be identified as non-target lesions. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter for all target lesions will be calculated and reported as the Baseline sum longest diameter.

Overall survival was defined as the time from the first administration of study drug to death.

A complete response was defined as the disappearance of all target lesions. A partial response was defined as at least a 30% decrease in the sum of the LD of target lesions taking as reference the Baseline sum LD. Stable disease was defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions at Baseline. All other lesions (or sites of disease) should be identified as non-target lesions. Target lesions should be selected on the basis of their size (lesions with the LD) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the LD for all target lesions will be calculated and reported as the Baseline sum LD.

Tumor necrosis was quantified in liver lesions greater than 2 cm at Baseline. When MRI showed many cut surfaces for a single tumor, tumor size and the size of necrotic area was measured by accumulation of the serial sections containing the tumor. Lipiodol accumulation in tumor after TACE was regarded as an indication of necrosis. Tumor necrosis was assessed at Baseline and 1 week prior to the next scheduled transarterial chemoembolisation (TACE) for the first 4 TACEs, then 1 week prior to every second TACE till disease progression. The extent of tumor necrosis is presented as the percentage of the tumor volume at Baseline.

Hoffmann-La Roche

Safety population: All participants who received at least 1 dose of study medication.

Bevacizumab 5 mg/kg

Age, Continuous

Sex: Female, Male

Intent-to-treat population: All participants who received study medication.

Medical Communications

Progression-free Survival

Percentage of Participants With an Objective Response

Time to Progression

Overall Survival

Percentage of Participants With a Best Overall Response of Complete Response, Partial Response, or Stable Disease

Lesion 1 (N= 29)

Lesion 2 (N= 11)

Lesion 3 (N= 5)

Lesion 4 (N= 5)

Lesion 5 (N= 4)

Tumor Necrosis

Overall Study

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Pembrolizumab

Immunomodulating Agents

Immune Checkpoint Inhibitors

* Pembrolizumab 200mg IV Q3W on day 1 of cycle 1 and 2
* Radio Frequency Ablation (RFA) / Microwave Ablation (MWA) / brachytherapy or combination of TACE with RFA, MWA or brachytherapy will be performed on day 1 of cycle 3
* Pembrolizumab 200mg IV administration 2 days after local ablation
* Pembrolizumab 200mg IV Q3W for up to 12 months total treatment duration

Local ablation via RFA will be performed via ultrasound- or CT-guided placement of a needle electrode / probe penetrating into the lesion center

Radio Frequency Ablation (RFA)

Local ablation via MWA will be performed via ultrasound- or CT-guided placement of a needle electrode / probe penetrating into the lesion center

Microwave Ablation (MWA)

Local ablation via brachythwerapy will be performed via ultrasound- or CT-guided placement of a needle electrode / probe penetrating into the lesion center

Brachytherapy

According to Investigator's choice, TACE using drug eluting beads can be performed combined with RFA, MWA or brachytherapy

Transarterial Chemoembolisation (TACE)

Salah-Eddin Al-Batran, Prof. Dr.

This is a multicenter, single arm, prospective, open-label phase II trial investigating the clinical activity of peri-interventional treatment with the anti-PD1 antibody pembrolizumab in HCC patients who are candidates for local ablation via either radiofrequency ablation (RFA) or microwave ablation (MWA) or brachytherapy or combination of TACE with RFA, MWA or brachytherapy.

The multimodal approach of combining peri-interventional administration of an immune checkpoint inhibitor and local ablation via RFA / MWA / brachytherapy or combination of TACE with RFA, MWA or brachytherapy harbors the potential to satisfy the unmet need for an improvement in the outcomes of HCC patients treated with RFA / MWA/ brachytherapy or combination of TACE with RFA, MWA or brachytherapy. Furthermore, early clinical data indicates that the combination of immune checkpoint inhibition with RFA, MWA or brachytherapy displays an acceptable safety profile, resulting in a positive benefit-risk ratio of this trial.

Immunotherapy with pembrolizumab in combination with local ablation

IMMULAB - Immunotherapy With Pembrolizumab in Combination With Local Ablation in Hepatocellular Carcinoma (HCC)

IMMULAB - A Phase II Trial of Immunotherapy With Pembrolizumab in Combination With Local Ablation for Patients With Early Stage Hepatocellular Carcinoma (HCC)

Evaluation of ORR according to RECIST 1.1 after two cycles of pembrolizumab and before performing local ablation will allow testing of the hypothesis that pre-interventional treatment with pembrolizumab before local ablation will result in conversion / downstaging of borderline candidates for local ablation. Furthermore, ORR is generally accepted as a valid endpoint for efficacy evaluation in one-armed trials without control group.

TTR and recurrence free survival, have meanwhile been accepted by medicinal agencies in drug approval processes as they allow for quicker efficacy assessment. This is most important in explorative clinical trials in early phases (like this phase II trial) as it allows for more rapid evaluation of the potential of new treatment approaches. Furthermore, many of these parameters are not influenced by follow-up therapies.

Overall survival will be evaluated and is still considered the gold standard for efficacy evaluation in clinical trials. Its major drawback is the potentially long observation period necessary for OS evaluation - especially in the curative setting as represented by the treatment approach in this trial.

Incidence and severity of adverse events according to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

Correlation analyses between selected molecular parameters and clinical data to identify molecular biomarkers like PD-1, PD-L1 and PD-L2) and immune cell infiltrates (like e.g. IGHM, CD3, CD8, FOXP3, CD68, CD205) as well as chemokines (CXCL9. CXCL10, CXCL13) and invasion markers (MMP7, MMP9) in tumor tissue and blood samples predictive for ORR, TTR, recurrence free survival and OS. Analyses will be performed by immunohistochemical and molecular methods in a central lab.

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Doxorubicin

Liposomal doxorubicin

Sorafenib

Angiogenesis Inducing Agents

Bilirubin

Protein Kinase Inhibitors

Enzyme Inhibitors

all patients will be treated with sorafenib

All patients will receive Sorafenib (800 mg/day) p.o. beginning two weeks before the first TACE and every day thereafter until patient death or premature withdrawal from study.

TACE will be carried out with doxorubicin (75 - 50 - 25 mg/m2, depending on serum bilirubin levels ≤ 1.5, 1.5 - 3, 3 - 5 mg/dL) : lipiodol (1:1) in a total volume of 20 mL; after administration of doxorubicin:lipiodol, additional embolisation will be carried out with bead block-endospheres. TACE will be repeated every 4 weeks for 3 cycles; additional cycles will be offered if clinically indicated (but no PEI or RF-ablation should be carried out after inclusion into the study)

Markus Peck-Radosavljevic, Prof. Dr.

Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a very poor prognosis. Aim of this open label single arm non randomized pilot trial is the evaluation of the efficacy and safety of sorafenib in combination with TACE in patients with unresectable HCC. Efficacy ad safety will be compared with a historical TACE-only group of a placebo controlled TACE-trial.

Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a very poor prognosis.

Aim 1: Efficacy of Sorafenib in combination with TACE TACE is an established therapy for patients with unresectable HCC and has been shown to significantly improve survival in these patients compared to no treatment. Quite often after cutting off the blood supply through the hepatic artery, the tumor induces active angiogenesis to promote collateral blood vessel growth from liver capsule arteries or collaterals from the gastroduodenal artery leading to tumor recovery and proliferation. Inhibition of this neoangiogenetic and proliferation activity after TACE by the multikinase inhibitor Sorafenib, already approved for HCC, could lead to significantly improvement in tumor control and survival in patients with advanced stage HCC.Safety will be compared with a historical TACE-only group of a placebo controlled TACE-trial.

Aim 2: Safety of Sorafenib in combination with TACE:

So far there are no reports about the safety of Sorafenib in combination with TACE. Here we evaluate the safety and tolerability of this combination until 12 weeks after the last TACE.

Aim 3: PPG-Measurement:

Development of portal hypertension in cirrhosis occurs due to two main pathophysiologic mechanisms: the increase in resistance to portal blood flow resulting from increased intrahepatic resistance and the decreased arteriolar vascular tone in the splanchnic vascular bed leading to increased splanchnic inflow of blood. Very recently, it has been shown that increased splanchnic inflow does not only result from arteriolar vasodilation due to excess NO-production in the splanchnic vascular bed but also from an increase in neoangiogenesis in the splanchnic circulation. Increased neovessel formation occurred within a few days of onset of portal hypertension both in a cirrhotic and an extrahepatic murine model of portal hypertension. Neoangiogenesis was effectively inhibited by either an antibody against VEGF-R2 or an inhibitor of VEGF-R2 autophosphorylation, resulting in a reduction of splanchnic blood flow.

Most recently, a combination of a VEGF and a PDGF blocker further decreased portal pressure in an experimental preclinical model.

As Sorafenib is a VEGF and PDGF blocker, we aim to analyze the influence of Sorafenib on portal hypertension and systemic and hepatic hemodynamics.

Aim 4: Biomarkers for treatment response:

Furthermore, we aim to analyze methylated tumor DNA in serum of patients with HCC undergoing Sorafenib treatment and TACE as possible marker of treatment response.

Sorafenib and Transarterial Chemoembolization for Hepatocellular Carcinoma

Sorafenib as Inhibitor of Collateral Tumor Vessel Growth During Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma (HCC)- a Pilot Trial to Evaluate Safety and Biological Response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Avastin (Bevacizumab) and Transarterial Chemoembolisation (TACE) Treatment in Patients With Liver Cancer	NCT00576199	Liver Cancer	Bevacizumab Transarterial c...	18 Years -	Hoffmann-La Roche
A Study of Avastin (Bevacizumab) and Transarterial Chemoembolisation (TACE) Treatment in Patients With Liver Cancer	NCT00576199	Liver Cancer	Bevacizumab Transarterial c...	18 Years -	Hoffmann-La Roche
IMMULAB - Immunotherapy With Pembrolizumab in Combination With Local Ablation in Hepatocellular Carcinoma (HCC)	NCT03753659	Hepatocellular ...	Pembrolizumab Radio Frequency... Microwave Ablat... Brachytherapy Transarterial C...	18 Years -	Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
IMMULAB - Immunotherapy With Pembrolizumab in Combination With Local Ablation in Hepatocellular Carcinoma (HCC)	NCT03753659	Hepatocellular ...	Pembrolizumab Radio Frequency... Microwave Ablat... Brachytherapy Transarterial C...	18 Years -	Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Sorafenib and Transarterial Chemoembolization for Hepatocellular Carcinoma	NCT00768937	Hepatocellular ...	Sorafenib Transarterial c...	18 Years -	Medical University of Vienna

Spots Global Cancer Trial Database for transarterial chemoembolisation (tace)